背景:胶质母细胞瘤(GB),最具侵袭性的脑癌,由于其对常规治疗的抵抗力,仍然是一个关键的临床挑战。这里,我们引入了局部区域靶向α疗法(TAT),该疗法具有针对鼠syndecan-1(SDC1)的大鼠单克隆抗体9E7.4与α发射器放射性核素astatine-211(211At-9E7.4)偶联。
方法:我们使用立体定向将50,000个小鼠GB的GL261细胞原位移植到同基因雌性C57BL/6JRj小鼠的右侧纹状体中。在第11天的肿瘤存在的MRI验证之后,在相同的坐标处注射TAT。生物分布,功效,毒性,应用本方案后,对局部和全身反应进行了评估.9E7.4单克隆抗体用碘125(125I)标记以进行生物分布,在其他实验中用astatine211(211At)标记。
结果:211At-9E7.4TAT在减少原位肿瘤方面表现出强大的功效,并在C57BL/6JRj模型中提高了生存率,以100kBq的最小活性达到高达70%。靶向SDC1确保了211At在最佳时间窗口内的脑保留,能够以最小的毒性进行低活性给药。此外,TAT大大减少了继发性肿瘤的发生,并在对侧再攻击后提供了对新肿瘤发展的抵抗力。通过激活中枢和效应记忆T细胞介导。
结论:局部区域211At-9E7.4TAT是所有临床前GB模型中最有效的TAT之一。这项研究将SDC1验证为GB的相关治疗靶标,并强调211At-9E7.4TAT是改善GB患者治疗和生活质量的有希望的进步。
背景:这项工作由法国国家研究局(ANR)“法国2030年投资计划”LabexIron[ANR-11-LABX-18-01]资助,SIRICILIAD[INCa-DGOS-INSERM-18011],法国计划“基础设施d”(法国生命成像)[ANR-11-INBS-0006],ANR的PIA3,融入“法国2030年投资计划”[ANR-21-RHUS-0012],以及InviscanSAS的支持(斯特拉斯堡,法国)。它还与:在EuroNanoMedIII(项目GLIOSILK)[ANR-19-ENM3-0003-01]的框架下的ANR;在Target项目的框架下的“RégionPays-de-la-Loire”;“国家对象癌”和“ComitéDéDistanaldeMaine-Targ”项目下的成像和放射疗法网络“法国”的“CanéropóleGrand-Ouest”(法国)。这项工作也得到了美国国家科学研究院(INSERM)的资助,南特大学,还有昂热大学.
BACKGROUND: Glioblastoma (GB), the most aggressive brain cancer, remains a critical clinical challenge due to its resistance to conventional treatments. Here, we introduce a locoregional targeted-α-therapy (TAT) with the rat monoclonal antibody 9E7.4 targeting murine syndecan-1 (SDC1) coupled to the α-emitter radionuclide astatine-211 (211At-9E7.4).
METHODS: We orthotopically transplanted 50,000 GL261 cells of murine GB into the right striatum of syngeneic female C57BL/6JRj mice using stereotaxis. After MRI validation of tumour presence at day 11, TAT was injected at the same coordinates. Biodistribution, efficacy, toxicity, local and systemic responses were assessed following application of this protocol. The 9E7.4 monoclonal antibody was labelled with iodine-125 (125I) for biodistribution and with astatine-211 (211At) for the other experiments.
RESULTS: The 211At-9E7.4 TAT demonstrated robust efficacy in reducing orthotopic tumours and achieved improved survival rates in the C57BL/6JRj model, reaching up to 70% with a minimal activity of 100 kBq. Targeting SDC1 ensured the cerebral retention of 211At over an optimal time window, enabling low-activity administration with a minimal toxicity profile. Moreover, TAT substantially reduced the occurrence of secondary tumours and provided resistance to new tumour development after contralateral rechallenge, mediated through the activation of central and effector memory T cells.
CONCLUSIONS: The locoregional 211At-9E7.4 TAT stands as one of the most efficient TAT across all preclinical GB models. This study validates SDC1 as a pertinent therapeutic target for GB and underscores 211At-9E7.4 TAT as a promising advancement to improve the treatment and quality of life for patients with GB.
BACKGROUND: This work was funded by the French National Agency for Research (ANR) \"France 2030 Investment Plan\" Labex Iron [ANR-11-LABX-18-01], The SIRIC ILIAD [INCa-DGOS-INSERM-18011], the French program \"Infrastructure d\'Avenir en Biologie-Santé\" (France Life Imaging) [ANR-11-INBS-0006], the PIA3 of the ANR, integrated to the \"France 2030 Investment Plan\" [ANR-21-RHUS-0012], and support from Inviscan SAS (Strasbourg, France). It was also related to: the ANR under the frame of EuroNanoMed III (project GLIOSILK) [ANR-19-ENM3-0003-01]; the \"Région Pays-de-la-Loire\" under the frame of the Target\'In project; the \"Ligue Nationale contre le Cancer\" and the \"Comité Départemental de Maine-et-Loire de la Ligue contre le Cancer\" (CD49) under the frame of the FusTarG project and the \"Tumour targeting, imaging and radio-therapies network\" of the \"Cancéropôle Grand-Ouest\" (France). This work was also funded by the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Nantes, and the University of Angers.